Inflammatory cytokines released by immune cells have been shown to act on the central nervous system (CNS) to control food intake and energy homeostasis. Decrease in food intake or anorexia is one of the most common symptoms of illness, injury or inflammation. The adipocyte-derived hormone, leptin, is considered a critical sensory anorexigenic mediator that signals to the brain changes in stored energy, determined by an altered balance between food intake and energy expenditure and has been shown to exert certain proinflammatory effects on immune cells. In contrast, ghrelin, the endogenous ligand for growth hormone secretagogue receptors (GHS-R), is produced primarily from stomach serving as a potent circulating orexigen controlling energy expenditure, adiposity and GH secretion. However, the functional role of ghrelin and GHS in immune cell function is unknown. Here, we report that GHS-R and ghrelin are expressed in human T lymphocytes, specifically localize in GM1-associated lipid rafts, exerts both specific and potent inhibitory effects on the TCR- and leptin-mediated expression of the proinflammatory cytokines via functional GHS-R and possible a novel GHS receptor on the surface of human mononuclear and T cells. Moreover, ghrelin administration into endotoxin challenged mice significantly inhibits inflammatory cytokine protein and mRNA expression in the serum and various organs. Furthermore, the expression of ghrelin, leptin and their receptors as well as GH appear to be significantly diminished with age within specific immune subsets and lymphoid organs, including the thymus. Administration of ghrelin, GH and leptin into aged mice using implanted osmotic pumps resulted in a partial reversal of thymic involution and restored thymic GH and IGF1 expression. Infusion of ghrelin, leptin or GH into old mice significantly improves the age-associated changes in thymic architecture and thymocyte counts along with an increase in recent thymic emigrants (RTE), an improvement of TCR diversity of peripheral CD4+ and CD8+ T cells and enhanced numbers of early thymocyte progenitors (ETP) and bone marrow-derived lineage negative sca-1, c-kit high (LSK) cells. Furthermore, the ghrelin and GHS-R deficient mice displayed enhanced age-associated thymic involution with reduced thymopoiesis, contraction of LSKs and major perturbations in the TCR repertoire of peripheral T lymphocytes. Our findings demonstrate a novel role for ghrelin and its receptor in thymic biology and T cell development. Moreover, our laboratory and others have demonstrated that the pituitary hormones, prolactin and human growth hormone, as well as insulin growth factor-1 (IGF1) potentiate human and rodent lymphocyte activation and proliferation in response to various antigens and stimuli both in vitro and in vivo. These hormones have also been shown to modulate a variety of leukocyte functions including potentiating lymphocyte activation and thymic engraftment and regeneration. Together, these data support the existence of a functional immunoregulatory network involving orexigenic and anorexigenic hormones that appear to play a significant role in cytokine regulation, cellular activation and survival. These data also support the potential therapeutic use of ghrelin and GHS-R agonists in the management of wasting associated with chronic inflammation and cancer and in restoration of thymic function in immunocompromised individuals.